Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities.
Trang 1S T U D Y P R O T O C O L Open Access
Study protocol for a cluster-randomized
trial to compare human papillomavirus
based cervical cancer screening in
community-health campaigns versus health
facilities in western Kenya
Megan J Huchko1*, James G Kahn2, Jennifer S Smith3, Robert A Hiatt2, Craig R Cohen4and Elizabeth Bukusi5,6
Abstract
Background: Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement
evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework
Methods: The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns Screening was done with human-papillomavirus testing
through self-collected specimens Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan This plan will be tested in an additional six communities in Phase 2 (enhanced intervention) We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies
Discussion: Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease
Trial registration: This trial is registered at ClinicalTrials.gov, NCT02124252
Keywords: Cervical cancer screening, Community health campaigns, Kenya, HPV self-collection, Implementation science
* Correspondence: megan.huchko@duke.edu
1 Duke University, Global Health Institute and Department of Obstetrics and
Gynecology, 310 Trent Drive, Room 204, Durham, NC 27708, USA
Full list of author information is available at the end of the article
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2Despite the fact that cervical cancer is highly preventable
through vaccination and organized screening programs,
over 500,000 women worldwide are diagnosed with the
disease every year [1] About 9 out of 10 cervical cancer
deaths occur in low-resource countries, with a particularly
high burden in sub-Saharan Africa, where the mortality
rate is 85% [2, 3] The inequality between high and
low-resource countries is mainly due to lack of screening in
low-resource countries, which lack the health care
infra-structure required for the cytology-based screening
pro-grams that have dramatically reduced the disease burden
in wealthier countries The World Health Organization
(WHO) recommends alternative cervical cancer
preven-tion techniques and protocols for low-resource countries
that employ low-cost or simple-to-use screening
technolo-gies [4] One such strategy– high-risk human
papilloma-virus (HPV) testing– has been shown to reduce the
incidence and mortality from cervical cancer when
coupled with outpatient treatment for women with
HPV-positive results [5]
In addition to effective screening tools, the impact of
cervical cancer prevention programs depends on two
main context-specific factors: (1) women’s access to
screening and (2) successful acquisition of treatment for
women who screen positive Access to both screening
and treatment is most challenging in poor rural areas,
due to geographic and infrastructure constraints [6, 7]
Most health care in rural areas takes place in small
health facilities with limited space, staffing, and
equip-ment, making it challenging to implement same-day
“screen & treat” strategies that have been proposed to
overcome barriers to treatment access [8] So, despite
the development of guidelines for cervical cancer
screen-ing that employed evidence-based technologies and
lower resource protocols, the lack of rigorously tested,
context-specific implementation strategies has left a gap
between policy and practice
In order to develop a context-specific, sustainable
im-plementation strategy, we undertook formative work to
identify local barriers and facilitators for cervical cancer
screening in government-supported health facilities in
rural western Kenya, an area of East Africa with a high
cervical cancer burden and screening rates as low as 3%
[9, 10] We found that access to screening was limited
by lapses in service availability and lack of clinic
attend-ance for preventive care [11] When services were
avail-able, both providers and patients found the need for a
pelvic exam limited the acceptability of cervical cancer
screening Based on the facility-based barriers, we
devel-oped and piloted a highly successful community health
campaign model for screening, consisting of outreach
followed by a brief campaign held in a central site in the
community, offering on-site screening and referrals for
treatment [12] An advantage of community-based screening is that only screen-positive women need to visit health facilities for follow-up care, reducing the visit burden for both woman and facilities, and allowing resources to be directed toward strategies to increase treatment uptake, such as intensified follow-up, trans-portation assistance or mobile units that bring treatment
to remote villages Thus, as has been seen in other health services [13–15], by combining community-screening with enhanced linkage strategies, our approach could maximize the health impact by increasing the number of women screening and the proportion successfully accessing treatment
To address the reluctance around pelvic exams, we chose to offer screening with self-collected specimens for HPV testing, an evidence-based strategy that would eliminate pelvic exams for initial screening, further increasing screening acceptance and efficiency We developed a study protocol that will allow us to compare two context-specific implementation strategies for an HPV-based cervical cancer prevention program through
a cluster-randomized trial of HPV-based cervical cancer screening in community-health campaigns versus health facilities using the RE-AIM framework [16, 17] This paper describes the study protocol (V 3.0, 20 July 2017) and the plan to evaluate the adaptability, comparative ef-fectiveness and cost-efef-fectiveness of these two strategies Methods
Study design and setting
The study is a two-phase cluster randomized trial in western Kenya to evaluate reach, effectiveness, cost-effectiveness and maintenance of two implementation strategies for a cervical cancer prevention protocol that consists of four critical, evidence-based components:
(1).HPV and cervical cancer outreach and education.In western Kenya, we found that women’s baseline knowledge and perception of cervical cancer risk is low; a brief educational intervention provided
by community health workers in primary care clinics improved these baseline factors and increased women’s intention to screen [18]
(2).HPV-testing using self-collected specimens with referral for treatment based on a single positive result.An HPV-based screening strategy is effective at reducing incidence of cervical pre-cancer and invasive cancer when women with screen-positive results undergo cryotherapy [5,19,20] Self-collected specimens are highly accurate, with comparable results
to provider-collection for the detection of high-grade cervical precancer [21–23] Women have consistently found self-sampling acceptable and preferable to provider-testing [24–26]; this finding has been
Trang 3supported in studies from sub-Saharan Africa [27,28].
Studies in various countries have shown that a
self-collection strategy increases screening uptake by
women not attending clinics [29–34]
(3).Notification of screening results using text
messaging.Based on our prior experience with
mobile health interventions [35,36] and the high
rates of cell phone use in western Kenya [37], HPV
test results were sent to all women via text message
with instructions about appropriate follow-up as
recommended by the Kenya Ministry of Health
guidelines
(4).Treatment with cryotherapy unless
contraindicated by cervical exam.Cryotherapy is a
low-cost, effective treatment method that can be safely
carried out by mid-level providers in low-resource
settings [38,39] Women who are not candidates for
cryotherapy (i.e lesions too large or abnormal cervical
anatomy) were offered Loop Electrosurgical Excision
Procedure carried out in the County Hospital
Together, HPV testing followed by cryotherapy for
women who test positive reflect the current WHO
recommendations [40]
In Phase 1 of this study, we compared two
implemen-tation strategies that incorporated these four
evidence-based elements of screening Based on our preliminary
data, we found that reaching and attending a health
facility for preventive care was a significant barrier to
screening for many women Therefore, the main
object-ive was to compare a model offering screening in brief,
high throughput community health campaigns to that of
a standard of care in which screening was offered in
local health facilities using the metrics defined in the
modified RE-AIM framework
In Fig 1, we present an overall schema of the
cluster-randomized trial In Phase 1, six communities were
ran-domized to the intervention: HPV screening carried out
in community health campaigns The remaining six
were comparison communities: HPV testing offered in government health facilities HPV-test positive women
in all communities were referred to the County hospital for immediate treatment, which is considered standard linkage to treatment
Development of an enhanced strategy for linkage to treatment: After Phase 1, we have an “phase inter-vention development” period in which we are evaluating the results from the trial The outcomes from the quali-tative and quantiquali-tative measures will be used to refine the screening intervention using context-specific details and develop an enhanced strategy for linkage to treat-ment Although we have identified factors that enable and inhibit women’s access to treatment, we chose to wait until after Phase 1 for the development of the enhanced strategy for linkage to treatment in order to truly work in partnership with the community The de-layed development of the linkage to treatment strategy has allowed us obtain a baseline measure of the efficacy
of standard referrals and identify factors that would in-fluence women’s access to care in this setting
After developing the strategy for enhanced linkage, we will pilot and then test the linkage to treatment strategy
as part of an“enhanced intervention” in the six commu-nities that served as controls in Phase 1 Using these communities for the enhanced intervention increases the efficiency of the study in two ways: i we will have done community enumeration and engagement, and ii
we will compare linkage to treatment outcomes from these “enhanced intervention” communities to the inter-vention communities from Phase 1
Study activities Study preparation
Community enumeration and randomization: Prior to the initiation of the cluster randomized trial, we characterized the study communities using
a combination of census data, health facility
Fig 1 Two-phase cluster-randomized trial design
Trang 4information, mapping and prospective demographic
data We identified communities of approximately
7500 people in three sub-counties of Migori County
in western Kenya (population: 350,000, 65
govern-ment health facilities) Population estimates were
calculated using the 2009 Kenyan census data with
population growth estimates for 2015 and 2014, a
method that was validated through door-to-door
enumeration for a recent large-scale community
randomized trial in rural western Kenya [41]
Eligible communities had at least one government
health facility with capacity to provide HPV testing,
support from community leaders for the community
outreach and/or health campaigns, accessibility to
health centers via a maintained transportation route
and sufficient distance from other potential study
sites to limit contamination between arms (buffer
zones) As our target group is women in rural
communities, we excluded urban settings or
communities in which the nearest health center is
Migori County Hospital and those that were taking
part in a cluster-randomized trial of large-scale
community-health campaigns for HIV-testing [41]
We conducted unmatched randomization using a
random number generator on Stata 10 The
unmatched design will allow us to consider the
relationship between community-level factors and
our outcomes of interest After communities were
chosen, population estimates were refined through
household enumeration done by community health
workers assigned to villages and sub-locations within
the communities
Provider and key stakeholder focus groups:
Clinicians and community health workers
(“providers”) within the community health
campaigns and health facilities participated in focus
group discussions to provide baseline data about
perceived barriers and strategies to facilitate HPV
screening uptake during the planning and
implementation adaptation period of the study
Although we sought key stakeholder input
throughout the development of the implementation
strategies, we held three focus group discussions
with key stakeholders in the intervention and
control communities for Phase 1 (community chiefs,
leaders of women’s groups, reproductive health
coordinator, medical superintendent and Charge
Nurse of Migori District Hospital) The goals of
these focus groups were to obtain a group
perspective on the intervention as planned for their
communities, any anticipated challenges and
strategies to optimize the screening strategy in both
arms Focus group discussions were analyzed using
the theoretical domains framework, which mapped
behaviors to intervention strategies, using evidence-based principles of behavior change [42]
Training and finalization of the screening protocol.We used educational modules piloted in western Kenya to provide standardized training in cervical cancer counseling and HPV-self testing to community health workers and clinicians [43] The community health workers received training in community outreach messaging, delivery of the educational module in the community health campaign setting, and teaching women how to perform self-collection of HPV specimens In addition to the general training, clinicians had undergone Ministry of Health-supported training to learn the cervical cancer screening protocol, including follow-up and pre-treatment exams Two nurses who had undergone cryotherapy training were identified and supervised for ten cryotherapies
at the County Hospital prior to study initiation
Cluster randomized trial: Phase 1
After community enumeration, training and protocol finalization, we launched the cluster-randomized trial in the six control and six intervention communities in Migori County (Figure 2) Phase 1 of the trial, consisting
of the activities listed below, took place over the course
of 1 year
Outreach and education:In all communities, information about cervical cancer screening and the opportunity to learn more about HPV-based testing were provided through community outreach, including fliers, posters and brief informational sessions in markets, churches and women’s group meetings Women and community leaders were provided with information on how to access cervical cancer screening in their community, e.g location of clinic or timing and location of community health campaign In all communities, women were invited
to participate in a brief, standardized cervical cancer education module, either at the health campaign or
in the health facility The module is approximately
15 min and covers topics ranging from simple anatomy, definition of cervical cancer and HPV, how screening works, what treatment is available for precancerous lesions, and how to perform HPV self-testing
Community-based testing (intervention group):
In six communities randomized to community-based HPV testing, community outreach teams carried out two-week community health campaigns in which HPV-testing was offered through self-collection In order to reach the entire community, the campaign moved to multiple sites over the two-week period,
Trang 5with approximately one to 2 days at each site The
campaigns consisted of health education and informed
consent, after which a health worker provided
additional instructions about self-collection and
recorded a mobile phone number before dispensing
the HPV testing kit The woman then would go to a
private area in the campaign tent to self-collect the
specimen and returned the completed collection kit to
the health worker prior to leaving
Clinic-based testing (comparison group):In the
six communities randomized to the control arm
(clinic-based testing), women were directed through
community outreach to go to their local health facility
during regular clinic hours to carry out screening At
the clinic, a health worker offered the educational
module, obtained informed consent and provided
additional information about self-collection, and
recorded a mobile phone number before dispensing
the HPV testing kit and instructions
HPV testing:While HPV test results are not the
primary outcome for this study, the accuracy and
reproducibility of measurements are essential for
outcomes in both arms and for modeling the impact
of the implementation strategies in larger populations We tested the DNA for 14 HPV types (16, 18, 32, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) using CareHPV™ testing system Collected
specimens were transported daily from the CHCs and weekly from the health facilities to the study lab
at Migori County Hospital Tests were run in batches of 90, with a turnover time of approximately
1–2 weeks for results
Notification of HPV results:HPV test results were preferentially sent to women via text message with instructions about appropriate follow-up as recommended by the Kenya Ministry of Health guidelines Messages were developed by key stakeholders and women from the target population during the focus group discussions Women who did not have access to a phone, or did not wish to receive their results by SMS could opt for a return visit to the clinic, or a home visit
Standard referral for treatment (both arms, Phase 1):Women who were HPV-positive were
Fig 2 Map of communities randomized to control and intervention activities in Migori, County Kenya This map was developed by Easter Olwanda, who has provided written permission for use in this publication
Trang 6referred to Migori County Hospital for a visual exam
with acetic acid and treatment with cryotherapy per
the WHO guidelines [44]
In-depth participant interviews and focus
groups:We conducted semi-structured interviews
with randomly selected participants in both arms at
three key points in the cervical cancer prevention
cascade: screening delivery (n = 30), notification of
results (n = 30) and treatment access (all) Participants
were contacted either in person or by phone, and
interviews conducted in person by experienced
qualitative interviewers in the local language using
interview guides developed by the research team
Topics explored in these interviews will elucidate ways
to make cervical cancer screening more acceptable and
accessible to women Interviews captured quantitative
data about women’s participation in various aspects of
the prevention cascade Interviewers then explored
women’s perspectives of their experience with the
intervention and explanatory factors related to the
decisions to access screening and treatment through
open-ended questions Among women who did not
access treatment, we probed for factors or strategies
that would allow them to link to care in the future
Provider and key stakeholder interviews and
focus groups:During the cluster- randomized trial,
providers in the community health campaigns
underwent brief interviews at two time points: after
three and six campaigns had been completed In the
clinic-arm, providers underwent interviews at three,
6 and 12 months into the intervention These
interviews will help to understand explanatory
factors for the success or failure of the intervention
from a health system perspective Interview topics
included personal attitudes and beliefs around
screening importance and feasibility, perceived and
actual barriers to implementation and potential
strategies to overcome provider, health delivery and
patient-level barriers to screening and treatment
Intervention development and cluster randomized trial:
Phase 2
Enhanced linkage to treatment:We will work
with health care providers, community members
and other stakeholders to review outcomes from the
quantitative, qualitative and process measures in
Phase 1, critically examine and modify the cervical
cancer screening strategy to develop and pilot the
enhanced linkage to treatment intervention over a
6–9 month period between Phase 1 and 2 We will
do this through a series of key stakeholder meetings,
followed by the establishment of smaller working
groups for the creation of the specific intervention
components In the first set of meetings, we will present the findings from Phase 1 and seek feedback
on representativeness and discuss implications for culturally relevant intervention strategies Options for the most feasible and acceptable strategies to increase the number of women linking to treatment will be explored in the light of that data
Criteria for potential strategies include: community-developed, low-cost, feasible in all study communities, and able to ensure treatment for HPV-positive women
in a timely manner in accordance with Ministry of Health guidelines In a second, small stakeholder meet-ing, we will review potential strategies discussed and developed in the first meeting, and discuss solutions proposed in other settings, including the use of mobile treatment units, transportation vouchers, and treatment
“navigators” to help women understand and travel to treatment sites Once the linkage intervention has been defined, we will hold another working group with stake-holders to create a standardized protocol, training man-ual, standard operating procedures and data collection instruments After equipment procurement, provider training and further outreach messaging, the enhanced linkage strategy will be piloted in two to three Phase 1 intervention communities prior to launch of Phase 2
Implementation framework
The study design, and outcome measures are centered
in the essential implementation metrics as defined by the RE-AIM framework, which modified to the context
of our study (Table 1) [17] Outcomes will be evaluated through quantitative, qualitative and process measures This design will allow us to test the following hypotheses:
Community-based cervical cancer screening will reach a larger portion of eligible women and be more acceptable to patients and providers than clinic-based testing (REACH)
A community-driven intervention will improve linkage to treatment among women who need treatment after an HPV-positive screening test compared to standard referral (EFFICACY)
We will identify modifiable patient and health system challenges that can be addressed to make health campaign based HPV testing and enhanced linkage to treatment succeed and be sustainable (ADOPTION & MAINTENANCE)
Community-based cervical cancer screening with enhanced linkage to treatment will have a greater population-level health impact as measured in women reached with screening and any necessary treatment, and favorable cost-effectiveness profile
Trang 7compared to clinic-based strategies and standard
referral for treatment (IMPLEMENTATION)
Participants
Our target population is women living in rural Kenya
who are eligible for and would benefit from cervical
can-cer screening per the Kenya Ministry of Health
Guide-lines (25–65 years old with an intact uterus and cervix)
The study population is women 25–65 years in the
twelve communities in the Nyanza Province who access
screening during both phases of the trial
Recruitment and consent
Communities participating in the trial provided verbal
assent in the planning process with written consent
ob-tained from individuals for screening Participants were
recruited through the community health campaigns and
in the clinics Women within the target age range were
invited to attend the cervical cancer educational module
After the health talk, women were asked to provide
in-formed consent by research assistants for a post-module
questionnaire and follow-up after screening completion
Women who were not willing to provide informed
con-sent were still able to attend the health talk and have
ac-cess to the HPV screening strategy assigned to her arm,
but were not contacted for the follow-up in-depth
inter-views or participation in focus group discussions
Primary and secondary endpoints
To determine the reach of cervical cancer screening
using HPV-testing in community health campaigns
compared to clinics, we are using the following metrics: i) the absolute number of women who completed screening in each arm and ii) the proportion of women
in each arm who completed screening The total number
of women in each arm is the number of women 25–65
in each community as determined by census data Secondary outcomes will include iii) the proportion of women who accept screening among women offered at each site and iv) the proportion of women in the clinic-based arm who request clinician-collected specimens
To determine the efficacy of a community-developed strategy to increase treatment access, we will compare the efficacy of the community-based HPV testing with standard versus enhanced linkage to treatment using the following metrics: i) the number of women who receive treatment after screening HPV + in the intervention (Phase 1) compared to the enhanced intervention (Phase 2) and ii) the proportion of HPV-positive women in each arm who complete treatment Secondary outcomes that address quality of care concerns for the models will include iii) the proportion of women who receive the correct treatment (per Ministry of Health protocol) during a single treatment visit and iv) the average time between HPV testing and access of treatment by arm
Data collection
We collected data on both screening and linkage to treatment from both control and intervention communi-ties in Phase 1 Data was collected by members of the research team and entered into pre-programmed tablet computers using OpenDataKit software (ODK™),(https://
Table 1 A modified RE-AIM framework to evaluate community health campaign-based cervical cancer screening compared to health-facility based screening
women in rural kenya?
A screening strategy offered through community health campaigns in a central location will reach a large proportion of reproductive-aged women How do we reach them?
Effectiveness Is the program effective? Are women getting screened for
cervical cancer with HPV?
A community-based strategy allowing for self-testing will be highly acceptable.
How do we ensure effectiveness? Are HPV + women successfully
linking to treatment?
Innovative, patient and provider-designed strategies will increase the number of women linking to care.
Adoption and
Maintenance
How can strategy be maintained
after initial implementation and
adopted in similar communities?
What are the patient, provider and delivery system processes necessary to ensure consistent service provision?
A screening protocol with a simple, patient-performed test offered as part
of a health fair will minimize the costs to the health care system to introduce screening What are the short and long-term
health effects in the community?
What is the population-level health impact
of screening using HPV self-testing in the CHCs with enhanced linkage to care?
The high number of at -risk women reached through the CHC-base strategy with enhanced linkage to care would produce a greater population-level health impact.
Implementation What is adherence to the
implementation strategy at
the delivery level?
Is HPV testing being offered and delivered consistently at the CHC and clinic sites?
Providing testing in a high-volume CHC will reach
a large number of women with low staffing and infrastructure needs, and will therefore have a lower cost per woman treated than a standard strategy.
What are the costs of
implementation?
What is the cost per lesion treated?
Trang 8opendatakit.org) which had been used by this research
team for the past several years Programming included
checks for range, structure, and internal consistency
During the community-health campaigns, data was
col-lected directly from providers and participants into the
tablets and was transferred daily via a secure electronic
transfer to our data center facility in Kisumu, Kenya and
stored on a secure server To capture visits and
out-comes from clinic-based screening and facility
treat-ment, a member of the research team visited each
clinical facility on a weekly basis to enter data from
Min-istry of Health registers and study-specific forms into
the tablets Data transfer from clinical-sites took place
weekly The same data collection procedures will be
ap-plied in Phase 2
Implementation consistency
All four basic components of the intervention (outreach/
education, HPV-testing, notification of results and
linkage to treatment) were monitored throughout Phase
I of the trial to ensure maintained fidelity to the protocol
and quality of service and message delivery Quantitative
outcome measures, as well as the process measures
listed below assessed continued fidelity of the
interven-tion as offered Qualitative data from in-depth
inter-views, focus-group discussions and process measures
will provide a more complete picture about subtle but
important factors that may influence the actual service
delivery and uptake
Sample size
Using estimates from the 2009 Kenya census [45] with
projected population growth for 2015 and results from
recent community-wide census enumeration carried out
by a cluster randomized trial in an adjacent district [46],
we have estimated the total available population of
women to be approximately 1000 per community of
5000 The estimates for attendance at community health
campaigns (60% or 600 women) and clinics (30% or 300
women) and screening uptake were based on our
forma-tive work, community health campaign attendance in
adjacent districts, and prior studies of self-collected
HPV testing [27, 28, 47] Our assumptions were that (1)
attendance would be higher at community health
cam-paigns and (2) screening uptake would be higher among
women attending community health campaigns because
most women attend based on outreach messaging
around cervical cancer These assumptions suggested a
study population of 510 women per community
acces-sing testing through community health campaigns and
210 accessing screening through clinics For Phase 1, the
total number of women accessing screening in the six
communities randomized to community health
campaigns would be 3060 and 1260 in communities
randomized to clinic-based testing We used these conservative estimates for sample size calculations (see below), but allocated resources for up to 4500 women in the community-testing arm and 2000 women in the clinic-based screening arm to ensure continuity of study activities We also enrolled all providers and targeted key ministry of health stakeholders for quantitative and qualitative assessments of barriers and facilitators to care A representative subset of this group were invited
to participate in meetings to develop the enhanced linkage intervention
Statistical analysis
Preliminary Analysis:For each outcome, we will produce descriptive statistics (frequencies, proportions, etc.) overall, across clusters of interest (community, clinic, provider, etc.), and over time
We will also graph these data to identify visual trends
Primary and Secondary Analysis:Although this is a community-level intervention, the main outcomes will be analyzed at the individual level We will compare the number and proportion of women who screen for HPV (reach) and who get treated for a positive HPV test (efficacy) in communities assigned
to community vs clinic-based testing using generalized estimating equations to account for the correlation among observations within communities Efficacy: We will employ a log link and Poisson distribution with an offset term to represent the size
of each community
Power calculations:We anticipate being able to observe a 30% difference in overall screening uptake between the control and intervention arms, a conservative estimate relative to previous cluster randomized trials The power calculations assume an alpha of 0.05, a beta of 0.20, and an intracluster correlation coefficient of 0.072 for screening and 0.11 for treatment, based on calculations from a cluster-randomized trial of HPV efficacy [5]
Cost-effectiveness analysis (maintenance)
We assessed the costs, population health impact, and incremental cost effectiveness of three intervention strat-egies (clinic-based screening with standard linkage to treatment; community screening with standard linkage; and will assess community screening with enhanced linkage) To do this, we undertook a micro-costing of the resources needed to carry out the activities in both arms in Phase 1 and 2 Costing included 1) personnel (including fringe benefits); 2) recurring supplies and services; 3) capital and equipment; and 4) facility space Intervention costs were assessed using a uniform cost
Trang 9data collection protocol to quantify resources used and
associated costs in each of the study sites
(community-health campaigns, clinics, laboratories and district
hospi-tals) Data was obtained through administrative record
review and interviews with administrative, finance and
human resources staff, supplemented by direct
observa-tion in a limited number of staff “time and motion”
studies in order to distinguish cervical cancer-related
activities from other health services delivered by the
same personnel Costs were summarized as total
program costs as well as costs per woman screened and
per HPV positive women treated
We observed study outcomes to estimate the health
outcomes associated with each screening and linkage
strategy Observed data include will include the number
of women screened and treated for high-risk HPV, the
proportion of women undergoing cryotherapy vs LEEP,
and the side effects associated with each treatment We
will find the best possible available data to estimate the
prevalence of various HPV-subtypes in the region, and
the associated risks of cervical intraepithelial neoplasia
(CIN), recurrence rates of CIN after treatment, and
inva-sive cancer in women with and without treatment We
will translate each health event into a standard metric of
burden of disease, Disability-Adjusted Life Years
(DALYs), which combines morbidity (and associated
disability) with premature mortality (lost“life years”)
We will use the micro-costing described above to
esti-mate several indices comparing costs to desired program
outcomes: cost per case of HPV detected; cost per case
of CIN detected; cost per woman successfully linked to
facilities for treatment; and cost per woman treated We
will construct a decision model to estimate the health
impact of HPV screening and linkage to treatment in a
population cohort of 1000 women This model will
explicitly portray the paths from HPV to detection (by
clinical presentation or screening), the risks of clinical
progression, and outcomes with and without treatment
(early or late) It will incorporate data on local
epidemi-ology (HPV prevalence and cervical cancer, from Phase
1 and existing surveillance data); the clinical course of
HPV and cervical cancer (from scientific literature); and
the effectiveness of treatment (with cryotherapy and LEEP,
as well as for more advanced disease, from scientific
literature) Model outcomes will include deaths from
cervical cancer, lost years of life, and morbidity (short and
long-term), and DALYs (disability adjusted life years)
We will use the decision-analysis model to assess the
incremental cost-effectiveness ratio (ICER), defined as
the added cost per DALY averted, when comparing
intervention strategies We will also calculate the ICER
compared to the current standard, which is no organized
available screening, using baseline data of screening
availability and use to calculate this We will also
estimate the costs for scaled-up replication, which will include variations in the number of and costs for personnel, community-health campaign structure and duration, HPV screening test costs laboratory costs and different linkage strategies
Process measures
We will use quantitative process analyses to evaluate the strategy implemented in both arms at four levels of the intervention delivery process (Fig 3) These include a) the proportion of women from each community health campaign offered HPV testing or referral (community health campaign-level processes); b) the proportion of HPV tests for which valid results are available (specimen transport and laboratory processes); c) the proportion of women who receive their test results (community health worker processes); and c) the proportion of HPV+ women attending a treatment visit who receive the appropriate treatment per Kenya Ministry of Health guidelines (health delivery center processes) We will use data from the provider and participant interviews and focus groups to explore the factors impacting the relevant service delivery processes that affect the overall result though quantitative and qualitative measures as well as explore additional key barriers and facilitators to both screening and treatment Focus group data will enrich these conclusions and be used to develop an enhanced linkage intervention
Ethical review
The trial was reviewed by an implementation and dissemination science section at the National Cancer Institute prior to funding Ethical approval was obtained
by the Committee for Human Research at the University
of California, San Francisco (#14–13,698), Duke University Institutional Review Board (Pro0007742), and the Scientific and Ethical Review Unit at the Kenya Medical Research Institute (SERU 2918) Any major protocol changes will be communicated to all three review boards and to the trial registry at ClinicalTrials.gov Complete trial registry data is available in a Additional file 1
Trial status
Focus Group Discussions and in-depth interviews with key informants took place in August and September
2015 A pilot campaign took place in December 2015 Screening activities and enrollment in Phase I of the cluster-randomized trial were carried out between January and September 2016 We are now sharing feedback
of Phase I results and observations with various stake-holders (community members, health care providers, and health management teams) in preparation for FGDs and working groups, which are aimed at enabling us design a strategy for enhanced linkage to treatment
Trang 10Substantial progress toward cervical cancer prevention
has been made through research validating low-cost
screening strategies that have been included in national
and international protocols and guidelines However, like
many international guidelines, the WHO cervical cancer
guidelines lacks advice on active implementation
strat-egies [48] While this is partly due to an emphasis on
the clinical portion of the guidelines, some of this can be
attributed to the lack of effective implementation
strat-egies Our goal with this novel study is to work with the
community using a rigorous implementation framework
to develop a strategy that could be scaled to improve
the reach and efficacy of cervical cancer prevention
programs in rural Africa, where the lack of health
care infrastructure and services has lead to poor
health outcomes We are also hoping that the
meth-odology of this project can be expanded to develop
implementation strategies that would help address
other health care needs
Based on our formative work, we expect that
community-based cervical cancer screening will reach a
substantially larger portion of eligible women than
clinic-based testing Our findings will help guide
imple-mentation and optimization of a community-based HPV
testing model While we anticipate that the
community-driven enhanced intervention will be more effective at
link-ing women to facilities for treatment than the standard
re-ferral system, this study will allow us to test both models
and look at various aspects of implementation, including
cost-effectiveness In addition to these findings, we will
provide a model for a successful strategy to link women to
treatment within cervical cancer screening program and to
provide program leaders and policymakers with a tool kit
to design and evaluate a context-specific enhanced linkage
strategy that could be implemented in their own settings
We expect that community-based HPV screening will have
a greater cost effectiveness and public health impact than clinic-based testing, and that enhanced linkage strategies will amplify these differences Overall, our findings will provide evidence to inform clinical protocols and govern-ment policy regarding the provision of cervical cancer pre-vention strategies and provide a guide for adaptation and evaluation of similar programs in other settings Ultimately programs that both use evidence-based techniques and reach a large proportion of the population will impact the millions of women at risk for cervical cancer in low re-source countries worldwide
Conclusions This project will have broad implications at both local and national policy and planning levels, given the enthusiasm of the Kenya Ministry of Health and Division of Reproductive Health to implement na-tional cervical cancer prevention strategies and their partnership in this project When the analyses are complete, we will have produced a comprehensive de-scription of barriers and facilitators to providing clinic and community-based cervical cancer screening through HPV testing, determined which strategy has greater reach and a better cost-effectiveness profile, and developed a strategy to improve linkage to treatment in partnership with the community If a community-based screening strategy is shown to have more reach with a favorable cost-effectiveness profile, this could be a viable strategy for roll-out in similar settings in Kenya and possibly for adap-tation to other East African countries with a high cervical cancer burdens Just as importantly, if community-based testing is more effective and scalable than clinic-based testing, we will explore factors necessary to improve access to clinic for cervical cancer screening and other preventive care services
Fig 3 Quantitative process measures for four aspects of cervical cancer prevention program delivery